For neurobiologist Yevgenia Kozorovitskiy, every answer has a question.
It’s an approach fundamental to her research on neuromodulators, a subset of neuronal communicators that help shape the way we live in many ways as yet unknown.
“Any behavior that a person can think of — from eating and sleeping to paying attention and setting long-term plans — is profoundly guided by neuromodulatory systems,” says Kozorovitskiy, whose research has earned numerous distinctions, including the Searle Scholar and Rita Allen Scholar awards. “Because of this, it’s no surprise that disturbances in this slower type of brain signaling are implicated in a host of neurodevelopmental, neurological, and mental health disorders.”
The human brain consists of billions of neurons wired together into intricate circuits by trillions of tiny junctures called synapses — the minute gaps between cells.
Crossing each synapse are signaling molecules known as neurotransmitters. These chemical messengers allow one neuron to communicate to another. One neuron produces an electrical action potential and releases fast-acting molecules that make downstream neurons more or less likely to “fire” an action potential themselves. In contrast to this fast method of electrochemical signaling, neuromodulators are a diverse group of molecules — including small molecules, peptides, and even gases — that can function on the broad order of milliseconds to hours. They can also affect large populations of neurons at once.
“Although we view these challenges through a basic science lens, why I do what I do is to one day affect clinical care,” says Kozorovitskiy, who joined Northwestern in 2014. “Our hope is to better humanity by learning how to fix the broken brain.”
Kozorovitskiy became interested in neuroscience as a career while an undergraduate at Princeton University in the late 1990s. After learning how plastic the brain remains even as it ages — new neurons are born throughout life — she was hooked on the field. Her studies on dendritic spines, which began when Kozorovitskiy was a postdoctoral fellow at Harvard, continue today in her lab at Northwestern. These spines, which can number 10,000 on a given neuron, are the small protrusions on the branched extensions of many nerve cells. They physically house a large proportion of excitatory synapses, or connections between neurons.
“Each protrusion is full of proteins that help maintain its structure and allow communication signals to spread very efficiently.” says Kozorovitskiy. “In addition to studying the propagation of these connections, we are developing ways to reproduce them in a relatively intact circuitry.”
Using lasers to activate single molecules of glutamate, a well-known neurotransmitter, Kozorovitskiy has been able to create dendritic spines on demand. The technique relies on powerful chemical compounds that are only activated when exposed to a specific light wavelength produced by a laser. Kozorovitskiy is investigating the amount of glutamate needed to create new spines and how neuromodulators guide this activity, so that scientists may one day co-opt the biological process to heal the brain. Dendritic spine loss is implicated in autism spectrum disorders, Alzheimer’s disease, and depression.
“It appears that a certain class of rapidly acting anti-depressant drugs seems to act by changing neuronal connections, so if we can induce them we can ask very specific questions about whether a new production of synapsis or maintenance of synapsis is responsible for how these drugs work,” says Kozorovitskiy. “The fact that we can use lasers to at-will create new connections in certain genetically targeted cells allows us to disambiguate the possibilities.”
To zoom in on individual dendritic spines and cellular organelles even more closely, Kozorovitskiy has collaborated with researchers like Hao Zhang, biomedical engineering, to develop new optical techniques for peering deeper inside the mouse brain and imaging faster at higher resolution. Many of the brain’s basic structures and functions are common across mammalian species. The team’s ongoing use of two-photon microscopy with structured illumination — a technique that relies on lasers to excite fluorescent tags — has produced intriguing results. The Kozorovitskiy lab uses optical tools and other techniques in ongoing investigations of multiple neuromodulators, focusing most on dopamine. This amine influences both movement and cognition, and the lab’s studies could one day lead to new ways of treating Parkinson’s disease.
“Northwestern and the Department of Neurobiology have been tremendous in building an atmosphere where cutting-edge neuroscience research is embedded within a supportive and collaborative environment,” says Kozorovitskiy. “Our work would also be impossible without the generous support of our sponsors, including the Arnold and Mabel Beckman Foundation, the Rita Allen Foundation, the Kinship Foundation, William M. and Bernice E. Bumpus Foundation, and others. “
The long-range goal of Kozorovitskiy’s lab is to accelerate understanding of synapse development and neuromodulation, and in turn facilitate the development of therapeutic applications by harnessing the power of neuromodulators to functionally reconfigure, and even rewire, neural circuits.
“For me, never being able to fully answer a question is in many ways the magic of science,” says Kozorovitskiy. “Being able to choose an initial inquiry, create information that wasn’t there before, and ask a novel question based on that information, is literally addictive.”